This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- DA-110: Determining if and how Adolescent Behaviors Affect Connections in the Developing Brain. The adverse impact of smoking on health is a world-wide epidemic that contributes to four million deaths a year, with an expected increase to 10 million per year world-wide by 2030. Tobacco dependence is viewed as a "pediatric disease" because most people begin smoking during adolescence. Adolescents display a greater sensitivity to the addictive effects of nicotine, becoming dependent upon smoking more rapidly than adults. Studies also show that smokers who began as adolescents smoke more frequently with a lower rate of quitting. Despite the many reports establishing a greater sensitivity of adolescent brains to nicotine, the fundamental basis of this greater sensitivity together with the long-term consequences of nicotine exposure on the wiring and neurochemistry of the brain is unknown. Most animal studies on adolescents have limited outcome measures of nicotine exposure to a single aspect such as behavior, agonist binding, or electrophysiological outcomes. Furthermore, none of the studies have examined plastic changes at the level of individual neurons with respect to the normal endogenous cholinergic system of the basal forebrain, and we know of no studies that integrate information from animal systems with human behavior. Thus, this Challenge Grant is a multidisciplinary approach that involves investigators from the fields of animal behavior, human cognition, genetic epidemiology, and molecular cell biology to test the validity of the following model: that the enhanced sensitivity of adolescents to nicotine is due to an imbalance between the endogenous cholinergic system and the function of nicotinic acetylcholine receptors (nAChRs). We predict that the cholinergic pathway from the basal forebrain to the cortex and hippocampus is not yet functionally mature in adolescents, yet an overabundance of terminals with nAChRs combined with a reduced level of prototoxin modulators of nAChRs allows exogenously administered nicotine to lead to long term changes that enhance reward pathways, while preventing full cholinergic maturation, leading to a beneficial effect of nicotine in cognitive performance that reinforces the use of nicotine. The specific aims of this application are: 1) to use adolescent and adult transgenic Thy-1-eYFP mice that demonstrate nicotine-induced conditioned place to determine whether changes in arborization of eYFP- labeled dendrites in layer 5 as well as changes in eYFP-terminals in nucleus accumbens occur;to determine if correlative changes in cholinergic innervation or dopaminergic interaction with eYFP-containing structures occur;2) to determine whether mice that lack or carry only one copy of the prototoxin gene psca exhibit a greater physiological and behavioral response to nicotine and to determine whether this correlates with parameters examined in Aim 1;3) to genotype human adolescent subjects that have been screened and tested for impulsivity, nicotine exposure, and drug abuse to determine whether specific alleles of prototoxin genes are correlated with increased impulsivity or nicotine dependence. PUBLIC HEALTH RELEVANCE: The adverse impact of smoking on health is a world-wide epidemic that contributes to four million deaths a year. Studies show that smokers who began as adolescents smoke more frequently with a lower rate of quitting. Despite the many reports establishing a greater sensitivity of adolescent brains to nicotine, the fundamental basis of this greater sensitivity together with the long-term consequences of nicotine exposure on the wiring and neurochemistry of the brain is unknown. A greater understanding of these will lead to possible preventive measures and therapies, having a significant long-term impact on human health.